The anticonvulsant ethosuximide disrupts sensory function to extend C. elegans lifespan.
Ethosuximide is a medication used to treat seizure disorders in humans, and we previously demonstrated that ethosuximide can delay age-related changes and extend the lifespan of the nematode Caenorhabditis elegans. The mechanism of action of ethosuximide in lifespan extension is unknown, and elucidating how ethosuximide functions is important for defining endogenous processes that influence lifespan and for exploring the potential of ethosuximide as a therapeutic for age-related diseases. To identify genes that mediate the activity of ethosuximide, we conducted a genetic screen and identified mutations in two genes, che-3 and osm-3, that cause resistance to ethosuximide-mediated toxicity. Mutations in che-3 and osm-3 cause defects in overlapping sets of chemosensory neurons, resulting in defective chemosensation and an extended lifespan. These findings suggest that ethosuximide extends lifespan by inhibiting the function of specific chemosensory neurons. This model is supported by the observation that ethosuximide-treated animals displayed numerous phenotypic similarities with mutants that have chemosensory defects, indicating that ethosuximide inhibits chemosensory function. Furthermore, ethosuximide extends lifespan by inhibiting chemosensation, since the long-lived osm-3 mutants were resistant to the lifespan extension caused by ethosuximide. These studies demonstrate a novel mechanism of action for a lifespan-extending drug and indicate that sensory perception has a critical role in controlling lifespan. Sensory perception also influences the lifespan of Drosophila, suggesting that sensory perception has an evolutionarily conserved role in lifespan control. These studies highlight the potential of ethosuximide and related drugs that modulate sensory perception to extend lifespan in diverse animals.
Collins
James J
JJ
Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA.
Evason
Kimberley
K
Pickett
Christopher L
CL
Schneider
Daniel L
DL
Kornfeld
Kerry
K
D000375:Aging / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D004398:Dyneins / Q000235:genetics / Q000378:metabolism; D005013:Ethosuximide / Q000494:pharmacology*; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000187:drug effects; D008969:Molecular Sequence Data; D009154:Mutation; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000502:physiology*
D000927:Anticonvulsants; D029742:Caenorhabditis elegans Proteins; C093002:OSM-3 protein, C elegans; D005013:Ethosuximide; C522228:Che-3 protein, C elegans; D004398:Dyneins; D016547:Kinesins